title: 5-HT3 antagonists derived from aminopyridazine-type muscarinic M1 agonists.
abstract: A conformational analysis, performed on muscarinic M1 agonists, identified four structural features characteristic of the muscarinic M1 pharmacophore: (i) a protonable basic or quaternary nitrogen acting as a cationic head; (ii) an electronegative dipole usually part of a planar mesomeric ester, amide, or amidine function which can be replaced by an ether (muscarine) or a dioxolane (AF 30); (iii) an intercharge distance of 5 +/- 0.5 A between the cationic head and the electronegative atom of the dipole; (iv) an elevation of 0.5 +/- 0.03 A of the cationic head over the plane containing the electronegative dipole. During a reinvestigation of the conformational behavior of published structures of 5-HT3 antagonists, similar features were observed for the 5-HT3 pharmacophore. However many 5-HT3 antagonists possess additional aromatic planes not present in the muscarinic M1 agonists. These observations brought us to predict the chemical modifications that would change muscarinic M1 agonists into 5-HT3 antagonists. Four of the predicted aminopyridazines were actually synthesized and submitted to testing. The observed IC50 values for 5-HT3 receptor binding ([3H] BRL 43694) ranged from 10 to 425 nM, whereas the affinities for the muscarinic receptor preparations ([3H] pirenzepine) layed over 10,000 nM. In electrophysiological studies the two most active compounds 10 and 13 produced antagonist-like effects on the 5-HT receptor channel complexes responsible for the generation of the rapidly desensitizing ionic currents, and agonist-like effects on those responsible for the slowly desensitizing components.
authors.affiliation: Laboratoire de Pharmacochimie Moléculaire (UPR 421 du CNRS), Université Louis Pasteur, Illkirch, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Rival
authors.forename: R
authors.initials: R
authors.lastname: Hoffmann
authors.forename: B
authors.initials: B
authors.lastname: Didier
authors.forename: V
authors.initials: V
authors.lastname: Rybaltchenko
authors.forename: J J
authors.initials: JJ
authors.lastname: Bourguignon
authors.forename: C G
authors.initials: CG
authors.lastname: Wermuth
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000737:chemistry*; D009206:Myocardium / Q000378:metabolism; D011487:Protein Conformation; D011724:Pyridazines / Q000737:chemistry*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D018721:Muscarinic Agonists; D011724:Pyridazines; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists